Solid-phase synthetic techniques, in which a reagent is immobilized on a polymeric material which is inert to the reagents and reaction conditions employed, as well as being insoluble in the media used, are important synthetic tools. A polymeric reagent has the advantage of ease of separation from low molecular weight reactants or products by filtration or selective precipitation. The polymeric reagent can also be used in excess to effect fast and quantitative reactions such as in the case of acylations, or a large excess of reactants may be used to drive the equilibrium of the reaction towards product formation to provide essentially quantitative conversion to product, as seen in solid phase peptide synthesis. A further advantage of supported reagents and catalysts is the fact that they are recyclable and that they lend easily to automated processes. In addition, supported analogs of toxic and odorous reagents are safer to use.
Diazacycloalkyl-2-carboxy derivatives, especially piperazine-2-carboxamide groups, are present in numerous pharmacologically active compounds including, for example, farnesyl protein transferase inhibitors (See International Application No. PCT/US96/04172); platelet aggregation inhibitors (See U.S. Pat. No. 4,923,870); Factor Xa inhibitors (See International Application No. PCT/GB97/000270); alpha 1 adrenorecptor antagonists (See International Application No. PCT/US96/15223); tachykinin receptor antagonists (See U.S. Pat. No. 5,344,830); and angiotensin II antagonists (See International Application Nos. PCT/US92/04189 and PCT/US94/05789). Thus, the development of new synthetic methodology for preparing piperazine-2-carboxamides, particularly solid phase synthetic techniques which are especially useful for synthesis of large numbers of compounds through automated parallel synthesis or combinatorial library generation, is central to the rapid discovery of new therapeutic agents containing this functionality.
The solid phase synthesis of piperazine-2-carboxamide compounds is described in Breitenbucher et al., Tetrahedron Lett., 1998, 39, 1295–1298, in DiIanni Carroll et al., Bioor. Med. Chem. Lett. 1998, 8, 3203 and in U.S. Pat. No. 5,734,054.